PROJECT SUMMARY As William Harvey wrote, Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her working apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual laws of nature by careful investigation of cases of rarer forms of diseases. In addition to the missed scientific opportunity, marginalization of those with undiagnosed conditions exacts a tremendous human toll on health, emotional well-being, family life, and finances. As the Coordinating Center for a new Undiagnosed Diseases Network, Harvard Medical School will support the expansion of the National Institutes of Health's Intramural Undiagnosed Diseases Program into a collaborative, integrated network of 5-7 additional clinical sites with the goals of developing effective protocols for the diagnosis and care of people with undiagnosed conditions, as well as advancing the study of undiagnosed conditions by sharing high quality laboratory and clinical data generated by the network. We will do this by leveraging our collective expertise and experience in managing multi-site studies, trans-institutional data sharing, data analysis, biomedical curation, diagnosing and caring for those with rare conditions, and performance review to serve as the scientific, organizational, and operational foundations of the integrated and collaborative research community across the network sites. In so doing, we will accomplish five aims: (1) Provide the infrastructure, support, curation, and scientific leadership for the principled harmonization of clinical protocols, data standards, data analysis, and quality improvement practices throughout the network; (2) Create infrastructure to identify and match patients and clinical teams with intra- and extra-network expertise and resources; (3) Establish content and infrastructure to support transitions in care following UDP evaluation for diagnosed and undiagnosed patients; (4) Perform and support network dissemination activities; and (5) Continually evaluate the performance of individual clinical sites as well as the network as a whole.